Apparatus for applying tissue sealant

ABSTRACT

A device and method for applying a fibrinogen-based tissue sealant to seamlessly connect human or animal tissues or organ parts, to seal wounds, stop bleeding and the like by mixing fibrin or fibrinogen with blood clot-promoting coagulation factors are disclosed. The device includes two cylindrical compartments for separately containing the separate fluid components of the sealant preparation, which are simultaneously displaced from the respective compartments by plungers commonly depressable with the same effective strokes. The plungers may be depressed directly or by a common mechanism (e.g., rack and pinion) for accurately controlling the rate of dispensing fluid. The cylindrical compartments are of the same or different cross-sectional area and are arranged either concentrically or side-by-side. The device further includes structure for merging the two fluid components within an outer sleeve housing an inner needle. The sleeve and needle contain conduits for the flow of the two fluid sealant components as they are expressed from the respective compartments. Also disclosed are a convenient device for filling the two compartments, structure for mixing the fluid components, and for atomizing the effluent sealant fluid stream (i.e., spraying).

This is a Divisional of Ser. No. 08/595,936 filed Feb. 6, 1996, now U.S.Pat. No. 5,814,022.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the design of an improveddelivery apparatus for applying two component fibrinogen/thrombin tissuesealants. More particularly, this invention is directed to the design ofan apparatus that is easy to use and to fill, that allows accuratedispensing of small volumes and rapid dispensing of large volumes oftissue sealant, that allows minimal dilution of the fibrinogencomponent, and that ensures thorough mixing of the two sealantcomponents, thus promoting rapid coagulation with a minimal amount ofthrombin to produce a homogeneous tissue sealant.

2. Discussion of the Background

Clotting of blood in vivo takes place by conversion of the solubleplasma protein fibrinogen into fibrin, which spontaneously polymerizesinto an insoluble gel matrix which may attach to adjacent tissue. Thegel matrix stops bleeding and stabilizes structures. Thrombin catalyzedconversion of fibrinogen to fibrin can be reproduced in vitro and hasgreat utility for adhering tissues and achieving hemostasis. Such fibrinsealants and fibrin glues are available commercially and are also madein blood processing laboratories. Preparation and use offibrinogen-based sealants have been extensively reviewed¹.

Fibrin sealants, fibrin glues and adhesives based on combiningfibrinogen-containing solutions with thrombin-containing solutions areused to reduce bleeding and restore hemostasis during surgicalprocedures. They have been known and in use for many years during whichtechnology has evolved significantly. For example, fibrin clots can bemade using different concentrations of fibrinogen in conjunction withthe thrombin solution². Subsequent developments in technology includecryoprecipitate fibrinogen³. Concentrated plasma can be used as thefibrinogen component in fibrin sealants⁴.

Similarly, various types of applicators for fibrin glue are known⁵. Anoptimal design is not obvious because of the chemical and biologicalproperties of the liquid resulting from combining fibrinogen andthrombin solutions. Because of the rapid polymerization upon intimateinteraction of fibrinogen and thrombin, it is important to keep separatethese two blood proteins until application to the site of use. Inpractice, the two components are typically dispensed simultaneously fromseparate syringes and brought together by means of an applicatormanifold.

For example, one syringe-type apparatus for applying a tissue adhesiveincludes a plurality of standardized one-way syringe bodies of syntheticmaterial⁶. Each syringe body accommodates a plunger and ends in a conus.The apparatus also includes a means for holding together the varioussyringe bodies, a guide rod, common actuating means and a headcollecting the coni of said syringe bodies. This design, however, doesnot appear prevent clogging when flow of materials is interrupted duringthe course of its use in applying these materials to a surface. Theconnecting head brings the two materials together and the materials thentravel together to a single mixing needle. Because of the rapidcoagulation of the materials on mixing, this arrangement facilitatesclogging of the apparatus (and in particular, the head or manifold),thus rendering the apparatus unusable.

In a later design, a medicinal gas is used to clear the mixing needleand address the clogging problem⁷. It is acknowledged that the tissueadhesive may set in the mixing needle in case of an interruption of theflow of the components during application or when using long and thinmixing needles. Consequently, the mixing needle must be exchangedimmediately (e.g., upon interruption of use). However, from a practicalperspective, the use of a medicinal gas is not suitable for mostsituations.

Similar arrangements/designs may be subject to the same deficiency,clogging. One design makes use of a ribbon-like separation means toconfine clogging to a disposable tip⁸. Another design has the usefulfeature of specifying that the two syringes have different crosssections⁹. This arrangement includes a plurality of syringe bodieshaving equal effective strokes, each of the syringe bodies ending injoining pieces; a piston in each syringe body for commonly actuatingthem; and a connecting head attached to the joining pieces of thesyringe bodies and provided with a separate conveying channel for eachof the components to be applied. In this design, one of said syringebodies has a cross-sectional area that is two to nine times larger thanthe cross-sectional area of the remaining syringe bodies. The largersyringe body contains an adhesive protein solution having a fibrinogencontent of from 3 to 12%.

One reason for this arrangement/design is that the strength of thesealant is proportional to the fibrinogen concentration. Further, sincecryoprecipitate fibrinogen is not very soluble a smaller volume ofthrombin solution is useful in making a gel with greater adhesive andtensile strength.

An alternative embodiment that may help to minimize the clogging problemarranges for the two components to meet and mix within a disposablemixing tip¹⁰. This apparatus includes a plurality of distinct, elongatechambers containing fluids, each chamber including a piston for forciblyejecting the fluid therefrom through a tapered nozzle; needle meanshaving a corresponding plurality of interior conduits for dispensingfluid from said nozzles; lock means including a ridge projecting aboutan exterior surface of each tapered nozzle; and releasable retainingmeans comprising a separable needle and a releasable retaining meanscomprising a separable needle block having a fluid conduit with aninterior groove for engaging a corresponding nozzle ridge and means forretaining associated needle means in sealing relationship with thechamber nozzles and the fluid conduits.

The apparatus, however, may be inappropriate for use in delicatemicrosurgical applications. Separation of the two components in separatechannels in the mixing tip is effective but not optimal.

It is known that the tensile and adhesive strengths of fibrin sealantsare best if the two solutions are mixed well, preferably rapidly tohomogeneity¹¹. One apparatus which addresses the clogging problemprevents commingling of the two sealant components until they reach thetreatment site¹². This apparatus, however, may not provide thorough andadequate mixing of the two solutions. The same limitation is found in anendoscope design¹³.

Moreover, all of the heretofore referenced patents similarly fail toeffectively address the issue of providing for thorough mixing of thesealant components during application, particularly if the apparatus isdesigned to overcome the clogging problem. This has two undesirableconsequences: (1) the resultant gel is inhomogeneous and not as strongas that resulting from homogeneously mixed solutions and (2) morethrombin may be required to ensure rapid gelling. Risks associated withuse of bovine thrombin make it undesirable to use excessive amounts. TheU.S. Food and Drug Administration has expressed concern overcoagulopathies associated with immunological reactions to commonly usedbovine thrombin preparations¹⁴. The risk of zoonotic diseasetransmission has prompted the United Kingdom, Ireland and France to banthe use of bovine thrombin.

A method for conversion of autologous fibrinogen to non-cross-linkedfibrin II or incomplete fibrinogen cleavage products (fibrin I or des BBfibrin, having one or the other of the two fibrinopeptides intact) usingan insolubilized enzyme addresses a need for a thrombin-free fibringlue¹⁵. The resulting unstabilized gel is dissolved by pH adjustment,separated from the insolublized enzyme, then mixed with buffer torestore conditions favorable to the repolymerization of the solubilizedfibrin monomer solution, thus avoiding the addition of any solubleforeign animal protein (thrombin) to effect gelation of the sealant. Asimilar single protein solution method uses a mixture of thrombin andfibrinogen with an agent that inhibits the clotting activity ofthrombin¹⁶.

Limitations of these two methods include their multi-step nature and theconsequent expense and time required to carry out the processes.Additionally, the molecular structure and physical and adhesiveproperties of the resultant gels are not likely to be equivalent tothose of naturally formed clots¹⁷.

Yet another limitation of previous applicator designs is that depressingsyringe plungers may render accurate dispensing of small volumes ofsealant (e. g., single drops) difficult. Proposed solutions to thisdifficulty include a dispenser with a push button actuator¹⁸ and adevice using a lever and ratchet and pawl mechanism¹⁹ to dispensesealant components by pressure so that small volumes can be dispensedduring delicate operations such as otological surgical procedures. Bothof these devices are limited by the inability to rapidly dispense largervolumes of sealant when required, thus falling short of practical volumeflexibility needs.

The use of unequal amounts of solutions within the syringe bodiesdispensed simultaneously advantageously allows for minimizing dilutionof the fibrinogen containing solution by the thrombin solution. However,filling the separate compartments with the respective sealant componentsand assembling the mechanical components comprising these devices can becomplicated and time consuming.

One applicator, designed to produce a mist of mixed components²⁰, issimilarly complicated to assemble and use. If care is not taken inassembly of the device, misalignment of the two syringes with respect tothe applicator device and incomplete sealing of the syringe Luer portsinto the docking ports of the applicator manifolds may occur. Inaddition, mixing takes place in a spray head which may clog after use.

Alternatively, the two components of a fibrinogen-based tissue sealantmay be applied as separate aerosols and mixed in the field²¹,22. Thesedevices may not allow for adequate mixing of the two sealant components,Consequently, greater amounts of thrombin and inferior gels may beproduced, a problem inherent in field mixing.

REFERENCES

The following references are incorporated herein by reference, in theirentireties or to any extent desired and/or necessary.

1. Matras, H. (1985). "Fibrin seal: the state of the art." J OralMaxillofac Surg 43(8): 605-11.

Sierra, D. H. (1993). "Fibrin sealant adhesive systems: a review oftheir chemistry, material properties and clinical applications." JBiomater Appl 7(4): 309-52.

Thompson, D. F., N. A. Letassy, et al. (1988). "Fibrin glue: a review ofits preparation, efficacy, and adverse effects as a topical hemostat."Drug Intell Clin Pharm 22(12): 946-52.

2. Ferry, J. D. and P. R. Morrison (1950). "Fibrin clots and methods forpreparing the same." U.S. Pat. No. 2,553,004.

3. Alterbaum, R. (1987). "Method and apparatus for use in preparation offibrinogen from a patient's blood." U.S. Pat. No. 4,714,457.

Lontz, J. F. (1995). "Phase Transfer Process For Producing Native PlasmaProtein Concentrates." U.S. Pat. No. 5,420,250.

Matras, H., H. P. Dinges, et al. (1972). "Zur nahtloseninterfaszikularen Nerventransplantation im Tierexperiment." Wein MedWoschtr 122(37): 517-523.

Rose, E. and A. Dresdale (1986). "Fibrin adhesive prepared as aconcentrate from single donor fresh frozen plasma." U.S. Pat. No.4,627,879.

4. Antanavich, R. and R. Dorian (1995). "Plasma concentrate and tissuesealant compositions . . . " U.S. patent application Ser. No.08/351,010.

5. See Section 4, pages 320-321, in Sierra, D. H. (1993). "Fibrinsealant adhesive systems: a review of their chemistry, materialproperties and clinical applications." J Biomater Appl 7(4): 309-52.

6. Redl, H. and G. Kriwetz (1982). "Apparatus for applying a tissueadhesive on the basis of human or animal proteins." U.S. Pat. No.4,359.049.

7. Redl, H. and G. Habison (1986). "Apparatus for Applying a tissueadhesive." U.S. Pat. NO. 4,631.055.

8. Keller, W. A. and S. A. Chen (1988). "Dispensing and mixingapparatus." U.S. Pat. No. 4,767,026.

9. Eibl, J., G. Hobbesian, et al. (1988). "Arrangement for applying atissue adhesive." U.S. Pat. No. 4,735,616.

10. Speer, S. J. (1977). "Packaging and dispensing kit." U.S. Pat. No.4,040,420.

11. Thompson, D. F., N. A. Letassy, et al. (1988). "Fibrin glue: areview of its preparation, efficacy, and adverse effects as a topicalhemostat." Drug Intell Clin Pharm 22(12): 946-52. See paragraph pp.948-9.

Redl, H., G. Schlag, et al. (1982). "Methods of Fibrin SealApplication." Thorac. cardiovasc. Surgeon 30: 223-227.

Redl, H. and G. Schlag (1986). Fibrin Sealant and Its Modes ofApplication. Fibrin Sealant in Operative Medicine. G. Schlad and H.Redl. Heidelberg, Springer-Verlag: 13-26.

Shimada, J., K. Mikami, et al. (1995). "Closure of leaks by fibringluing. Effects of various application techniques and temperatures." JCardiovasc Surg (Torino) 36(2): 181-4.

12. Miller, C. H., J. H. Altshuler, et al. (1989). "Fibrin glue deliverysystem." U.S. Pat. No. 4,874,368.

13. Maslanka, H. (1990). "Injection equipment with a twin tubular needlefor an endoscope." U.S. Pat. No. 4,932,942.

14. Alving, B. M., M. J. Weinstein, et al. (1995). "Fibrin sealant:summary of a conference on characteristics and clinical uses."Transfusion 35(9): 783-90.

15. Edwardson, P. A. D., J. E. Fairbrother, et al. (1993). "Fibrinsealant compositions and method for utilizing same." EP (Application)U.S. Pat. No. 592.242.

16. Morse, B. S., R. T. McNally, et al. (1994). "Fibrin sealant deliverykit." U.S. Pat. No. 5,318,524.

17. Sporn, L. A., L. A. Bunce, et al. (1995). "Cell proliferation onfibrin: modulation by fibrinopeptide cleavage." Blood 86(5): 1802-10.

18. Tang, R. A. (1986). A New Application Method for Fibrin Sealant: TheGlue Gun. Fibrin Sealant in Operative Medicine. G. Schlad and H. Redl.Heidelberg, Springer-Verlag.

19. Epstein, G. H. (1993). "Method and apparatus for preparingfibrinogen adhesive from whole blood." U.S. Pat. No. 5,226,877.

20. Capozzi, E., and H. S. Cooksten (1992). "Biological syringe system."U.S. Pat. No. 5,116,315.

Capozzi, E., and H. S. Cooksten (1990). "Biological syringe system."U.S. Pat. No. 4,978,336.

21. Avoy, D. R. (1990). "Fibrinogen dispensing kit." U.S. Pat. No.4,902,281.

22. Lonneman, A. and C. H. Miller (1994). "Sprayer assembly forphysiologic glue." U.S. Pat. No. 5,368,563.

OBJECTS OF THE INVENTION

The present invention disclosed herein addresses and solves thelimitation of the prior devices. The present applicator is easy toassemble, can accurately dispense small volumes or rapidly dispenselarge volumes of sealant, minimizes dilution of the fibrinogencomponent, adequately mixes the two components, does not clog event whenset aside for several minutes, and is relatively easy to fill, assemble,use and manufacture.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 shows an embodiment of the present invention employing twosyringes 1 and 8 affixed in a bracket 2 with rack and pinion drive 3,manifold or body 4 with optional replaceable applicator static mixingtip 5. Syringes 1 and 8 are affixed to bracket 2. Syringe plungers 6 and9 are depressed by movement of the rack 7.

FIG. 2 shows a side view of and embodiment of the bracket 2 and rack andpinion drive 3. Syringes 1 and 8 are affixed to bracket 2. Rack 3 can bedepressed directly to rapidly dispense larger volumes of sealant, or thethumb wheel pinion 14 can be turned to displace small volumesaccurately. Syringe plungers are depressed by movement of the rack.

FIGS. 3A, 3B and 3C show cross sections of three arrangements for theseparate compartments for containing and dispensing the separatefibrinogen and gel-forming agent solutions: FIG. 3A shows syringes 1 and8 held together side-by-side in a bracket as shown in FIGS. 1 and 2;FIG. 3B shows integral side-by-side cylinders 15, made from a singlemold; FIG. 3C shows and embodiment comprising coaxially arrangedcylinders 10 and 11. The fibrinogen solution is put in the compartmentwith the larger cross section 12 and the thrombin and/or calciumsolution is put in the compartment with the smaller cross section 13.

FIG. 4 is a cross-sectional view of an embodiment of the manifold 4 withapplicator static mixer tip 5 of the syringe of FIG. 1. Swivel Luerlocks 21 provide a means for attaching the syringes. Thrombin isdispensed through the inner needle 22 and fibrinogen through the void orinternal passageway 23 between inner needle 22 and outer sleeve ortubular dispenser 25. Inserted static mixer device 26 fits snugly withinthe outer sleeve 25. Notched rings 28 on the rod mixer device ensuremixing of the two sealant components by creating turbulent flow. Thedistal tip 24 of the inner needle is located within the outer sleevenear the mixing device insert 26.

FIG. 5 shows a cross-sectional view of coaxially arranged cylindricalcompartments as shown in FIG. 3C. The inner syringe 32 containingthrombin solution is coaxial with the large syringe 31 containingfibrinogen solution. The inner syringe plunger 34 operates normally,traveling through a hole or slot in the plunger for the outercompartment 35. The cylinders are maintained coaxial with a cylindricalwasher 38 made of rubber of other suitable material. The needle-likemember or needle 37 leading from the inner compartment 40 conducts thethrombin through an opening into the replaceable mixing tip 39.

FIG. 6 is a detailed cross-sectional view of the lower part of thecoaxial syringe shown in FIG. 5. The mixing tip is removed. The needle37 leading from the inner compartment 40 exits through the center of amale Luer lock or fitting member 42. The fibrinogen solution in theouter compartment is conducted through a channel 41 in the washer 38 andexits from the male Luer lock around the inner chamber needle 37.

FIG. 7 is a cross-sectional view of an embodiment of a filling device (a"connecting tee") used to fill the two compartments of the coaxialsyringe shown in FIG. 5. A female Luer lock or fitting member 53 isjoined with the male on the syringe 42. The needle 37 from the innerchamber 40 pierces a rubber septum or fluid tight membrane 52. The innerneedle tip 39 may then be used to fill the inner compartment (e.g. bypiercing a septum on a container containing the gel-forming agentsolution). The outer compartment may then be filled with fibrinogensolution by fluidly connecting a chamber containing fibrinogen solutionto a male Luer lock or fitting member 51.

FIGS. 8, 9, 10 and 11 each show cross-sectional views of variousembodiments of the manifolds and mixing tips of the present apparatusfor applying tissue sealant. In all cases, the coaxial syringe shown inFIG. 5 is used. A Luer lock 42 is used to attach each of the fourapplicator tips to the double syringe.

FIG. 8 shows a disposable static mixer tip 26 essentially identical tothe one in FIG. 4.

FIG. 9 shows a flexible double lumen catheter 62 for application oftissue sealant at a distance from the syringe, (e.g., in a body cavitymade accessible by laparotomy). The Luer lock 61 allows attachment ofthe double lumen catheter 62 to the syringe, permitting separation ofthe solutions as they travel through the catheter 62. The catheter endswith a disposable static mixer tip 26 essentially identical to the onein FIG. 4.

FIG. 10 shows a spray tip 71. The two components mix in the tip 71 andthe mixture is nebulized by a small orifice 72.

FIG. 11 shows a simple mixing needle tip 81 that does not clog, even ifone intermittently applies sealant using the same applicator andcomponent solutions.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention concerns, in part, a dispenser comprising:

a plurality of separate parallel cylindrical compartments of the same ordifferent cross sectional area, arranged concentrically or side-by-side,each of said cylindrical compartments having an outlet port at one end,

a number of plungers equal to said plurality of cylindricalcompartments, and

a manifold having separate means for transporting fluid through themanifold from the outlet port of each cylindrical compartment to acommon location on the surface of the manifold opposite said outletports.

In further embodiments, the dispenser may further comprise a means forseparately or commonly actuating said plungers in mechanical connectionto said plungers, preferably both a means for commonly actuating saidplungers and a means for separately actuating said plungers. The meansfor commonly actuating said plungers may comprise a rack and pinionmechanism. Alternatively, the means for commonly actuating said plungerscomprises a bar, rod or other means for mechanically connecting saidpinion to the cap of each plunger.

The cylindrical compartments of the dispenser may be coaxial, and saidmeans for commonly actuating said plungers and said means for separatelyactuating said plungers may comprise a coaxial inner plunger having acap and a coaxial outer plunger having a coaxial cylindrical void intowhich said inner plunger is located, the diameter of said cap beinggreater than the diameter of said cylindrical void. In other words, thecylindrical compartments may comprise inner and outer concentriccompartments, the inner concentric cylindrical compartment being fittedwith an inner plunger, and the outer concentric compartment being fittedwith a cylindrical plunger having a coaxial cylindrical void withinwhich said inner plunger is located.

In one embodiment, the present dispenser comprises two coaxial cylindersof different sizes. When the plurality of cylinders is 2, said cylindersmay have equal heights, and the volume ratio of said cylinders may be 9or more, preferably 10 or greater. In the present application, "coaxialcylinders" refers to cylinders which share a common axis, or parallelcylinders of different diameters in which the void of the smallercylinder is contained within the larger cylinder.

The present dispenser may further comprise a manifold comprisingseparate inner and outer means for conveying the contents of saidcylinders to a common outlet, wherein the inner means extends furtherthan the outer means. The present dispenser may also further comprise adisposable tip which promotes mixing of said contents of the cylinders.In addition, the present dispenser may further comprising a means foratomizing effluent fluid in fluid connection to one end of saidcylindrical fluid conduit.

Fibrinogen and thrombin solutions are contained separately withincompartments in an apparatus comprising: (1) syringes held togetherside-by-side in a bracket, the plungers of said syringes commonlyactuable or depressible by an activating means or (2) integralside-by-side cylinders fitted with coupled plungers for simultaneouslyexpressing or dispensing the contents of said cylinders or, preferably,(3) coaxially arranged cylinders fitted with commonly (or separably)depressible or actuable plungers, the outermost of which is shaped toseal against both the inner wall of the outer cylinder and the outerwall of the inner cylinder.

Other factors being constant, tensile and adhesive strengths of tissuesealant are generally proportional to the concentration of fibrinogenafter combination with thrombin. To minimize dilution of fibrinogen bythe thrombin solution, the cross-sectional areas of the two compartmentsare preferably different so that a common stroke will displace a smallamount of thrombin solution relative to fibrinogen solution. Any ratioof cross-sectional areas is workable. A ratio of cross-sectional areasof greater than 1:5 is preferable and a ratio of 1:10 up to 1:40 is mostpreferable.

The volume of the compartments may vary depending on the intended use.Tissue sealants are typically dispensed from fibrinogen preparations ofvolume ranging from 0.5 cc to 5 cc. As described above, thecorresponding thrombin compartment typically would have a volume of onetenth to one fortieth the volume of the fibrinogen compartment.

In the embodiments of the present apparatus comprising side-by-sidesyringes or cylinders, to facilitate assembly, convenient fittings suchas swivel Luer lock fittings or the like are provided for coupling to amanifold so that coupling can be effected without the necessity ofrotating the syringes or cylinders relative to the assembly fixture andmanifold. Alternatively, the two syringes or cylinders terminate inneedles which may serve the dual functions of (1) facilitating fillingwith appropriate components of the fibrin sealant and (2) connecting toa manifold fitted with septa to mate with the needles, allowing fluidcommunication between the respective compartments and appropriatechannels within the manifold.

A further aspect of the present invention concerns a manifold forcombining the contents of a multicomponent dispenser, comprising

a first inlet port,

an inner fluid transport means in fluid connection with said first inletport, said inner fluid transport means having a first outlet portlocated at the end opposite said first inlet port,

a second inlet port distinct from the first inlet port, and

an outer fluid transport means in fluid communication with said secondinlet port, said outer fluid transport means having a second fluidoutlet port located at the end opposite said second inlet port,

wherein said second fluid outlet port is in the same location as saidfirst outlet port and at least part of said inner fluid transport meansis located within said outer fluid transport means.

In more specific embodiments of the manifold, the inner fluid transportmeans and said first inlet port comprise a hypodermic needle, and saidsecond inlet port and said outer fluid transport means comprises achannel in a solid material through which said hypodermic needle islocated or is able to penetrate (see FIG. 4).

In order to minimize the problem of plugging due to coagulation ofsealant within the manifold, the manifold is configured in such a way asto prevent commingling of the two sealant components until theexpression of one component, through a needle or the like whichseparately conducts said component, into a flow of the second componentwithin a sleeve, e.g. a larger bore hypodermic needle or the like, whichsurrounds said first hypodermic needle, the outer sleeve terminating ata point distal to the point at which commingling of the two fluids firstoccurs.

The needle conducting the lower-volume (e.g., thrombin) solution may bea standard 22 gauge needle, and the larger bore needle conducting thehigher-volume (e.g., fibrinogen) solution may be a standard 18 gaugeneedle. The larger needle may be of any size from 3 to 25 gauge, andfrom 0.5 cm to 6 cm in length, preferably 1 to 3 cm. The smaller needlemust fit within the larger and not obstruct flow.

In a further embodiment of the present apparatus comprising coaxiallyarranged cylinders, the contents of the inner compartment are in fluidcommunication with a hypodermic needle or the like which extends beyondthe distal terminus of a coaxial effluent port of the outer compartmentand which is of an outer diameter less than the inner diameter of saideffluent port. The contents of said outer compartment are isolated fromthose of the inner compartment, but are in fluid communication with theeffluent port of the outer compartment. By means of a Luer fitting orthe like, an outer sleeve comprising a hypodermic needle or the like, ofgreater internal diameter than the outer diameter of the innerhypodermic needle described above, is affixed to the effluent port ofthe outer compartment. The outer sleeve extends beyond the distalterminus of the inner hypodermic needle. The volume of the compartmentsmay vary depending on the intended use. Tissue sealants are typicallydispensed from fibrinogen preparations of volume ranging from 0.5 cc to5 cc. As described above, the corresponding thrombin compartmenttypically would have a volume of one tenth to one fortieth.

By commonly depressing the respective plungers of the inner and outercompartments, the contents of the separate compartments are expressed,dispensed or exhausted separately but simultaneously through the innerhypodermic needle and the outer sleeve. As they are expressed, the twoseparate fluid components merge at the distal terminus of the innerhypodermic needle within the outer sleeve. The merged fluids commingleand become mixed as they flow within the outer sleeve towards the distalterminus, becoming more thoroughly mixed by the time they are applied tothe site of use. If flow is interrupted during sealant dispensing , agel may form in the outer sleeve at a location between the distalterminus of the inner hypodermic needle to the distal terminus of theouter sleeve. The gel typically forms a short cylinder in the voidwithin the outer sleeve and does not substantially adhere to thematerial of the outer sleeve or inner needle. Rather, the short gelcylinder extends from the distal terminus of the inner needle toward thedistal terminus of the outer sleeve. Because of its shape, small sizeand lack of adherence to the surrounding outer sleeve, the gel which mayform does not effectively plug the device and can be dispensed orexpressed by resuming application of sealant without exertingperceptibly greater force to depress the commonly actuated plungers.

Mixing of the two fluid components as they are extruded is adequate formost applications, yielding strong gels which rapidly polymerize at lowthrombin concentrations. Optionally, if perfectly homogeneous mixing ofthe two fluid components is desirable, the outer sleeve may incorporatea static mixer comprising, for example, of parallel arcs centered on theaxis of a shaft cylindrical member or snugly fitted to the inner wall ofthe outer sleeve from a point just distal to the distal terminus of theinner hypodermic needle and extending to a point proximal to the distalterminus of the outer sleeve. Thus, the present invention also concernsa static mixing means, comprising:

a cylindrical fluid conduit,

a coaxial shaft having parallel arcs thereon, fitted within saidcylindrical fluid conduit, wherein said parallel arcs promote mixing ofsaid fluid.

Adjacent arcs may be rotated about the axis of the cylindrical member orcylinder to force a more tortuous and turbulent flow of the commingledfluids. Preferably, the arcs are positioned along the mixing tip so thatthe gaps of the rings are located opposite the gaps of the adjacentrings. Most preferably, the gaps on adjacent rings are on oppositesides. The static mixing insert may be of any length from 0.1 cm to 5cm, preferably 0.25 to 1 cm. The number of arcs may range from two tofifty, preferably five to fifteen. Thus, each arc of the present mixingmeans may comprise a ring having a void of from 5 to 90°, the void ofone ring being located opposite the void on adjacent ring(s).

On interruption of flow, coagulation of the sealant about the staticmixer will occlude the flow path. Removing and replacing the outersleeve and static mixer may be necessary in this embodiment. However,the combination of the outer sleeve and static mixer is inexpensive, andthe method of removing and replacing this combination is a very simpleoperation which sacrifices a minute included volume of sealant and iscompletely effective in restoring functionality of the applicatordevice.

Prior to dispensing sealant as variously described above, the separatefibrinogen solution and thrombin or other clot-promoting solutions mustbe charged into the respective applicator compartments. For thispurpose, a connecting tee can be used to direct the flow of the twosolutions separately into the appropriate compartments.

Thus, a further aspect of the present invention concerns a device forfilling a two-compartment dispenser, comprising

a first means for fluidly connecting said device with an outlet port ofa first container for fluid,

a first means for transporting fluid from said first means for fluidlyconnecting said device to a first compartment of said dispenser,

a second means for fluidly connecting said device to a second containerfor fluid,

a second means for transporting fluid through said device from saidsecond means for fluidly connecting said device to an outlet port forthe other of said two compartments of said dispenser.

A more specific embodiment of the device for filling the presentdispenser may comprise

a cylindrical shaft having a Luer fitting at one end and a pierceableseptum at the other end, and

a Luer fitting attached to the outer wall of said cylindrical shaft.

As shown in FIG. 7, the tee comprises a female Luer coupling 53 orequivalent means for docking with the effluent port 42 of the outercompartment. The inner hypodermic needle 37 is directed through thiscoupling and pierces a septum 52 which seals the opposing end of the teeso that said hypodermic needle passes in a straight path through the teeand isolates its contents from the void within the tee and is freebeyond the tee to collect the appropriate solution. The tee must beshort enough that the needle pierces the septum but should not haveexcessive volume. The length thus may be as little as 0.5 cm and may beas long as slightly shorter than the inner needle. Preferably, the teeis 1.5 to 3 cm in length.

The inner plunger is separably actuable from the outer plunger and ispulled back separately from the outer plunger to withdraw appropriatesolution from a source into the inner compartment. The orthogonal arm ofthe tee can be fitted with a hypodermic needle or tubing or the like. Byseparately pulling back the outer plunger, the second sealant componentis withdrawn from a source through said hypodermic needle or tubing orthe like and into the outer compartment. Alternatively, both solutionscan be separately and simultaneously introduced into the appropriatecompartments by pulling back simultaneously on both plungers while theinner hypodermic needle and appropriate means for the orthogonal arm ofthe tee to communicate fluidly with an appropriate fluid componentsource are simultaneously in separate fluid communication with therespective sealant component sources. The plungers are so arranged thateach may be separately pulled back or both together.

The inner and outer plungers are separably actuable by virtue of anarrangement whereby the inner plunger moves freely and independentlywithin a hollow outer plunger (i.e., the outer plunger contains acylindrical void within which the inner plunger is located). The top ofthe outer plunger may comprise a button with a center opening ofsufficient diameter to allow the inner plunger to move freely. A buttonon the top of the inner plunger, however, which is larger than theopening in the top of the outer plunger button engages the two plungersto move in concert when the upper plunger is depressed and encountersthe outer plunger button. In other words, the hole in the center of theouter plunger has a diameter smaller than the diameter of the innerplunger button (e.g., insufficient to allow the inner plunger button totravel further without simultaneously effecting an equal stroke of theouter plunger). The bases of the inner and outer cylinders are taperedin such a way as to conduct air entrapped within the two compartments toa high point communicating with the respective effluent channels whenthe apparatus is inverted, thus permitting entrapped air to be expelledafter filling and before application of sealant to the site of use.

To permit accurately controlled dispensing of small volumes of sealant(e.g., single drops), depression of the commonly actuable plungers ofany of the above described embodiments may be effected by a means fordepressing the plungers (e.g., a rack and pinion mechanism driven, forexample, by a thumb wheel pinion as shown in FIG. 2). When rapiddispensing of sealant is desired, said rack can be depressed directly.The rack and pinion may be used with any of the three cylinderarrangements previously described.

When a spray sealant is desired, any of the above described embodimentsmay further comprise an atomizing nozzle at the outlet port. Mixingoccurs before atomization, assuring homogeneous sealant and thestrongest gel while using a minimal amount of thrombin. However,interrupting sealant flow may lead to clogging the atomizing attachmentand may thereby necessitate replacing the atomizing attachment.

Thus, either the present dispenser or the present mixing means mayfurther comprise a means for atomizing effluent fluid in fluidconnection to one end of said cylindrical fluid conduit in the means forapplying the mixed fluids to the desired site of application.

A further aspect of the present invention concerns a method for applyingtwo or more solutions of reactive components to a common site,comprising:

filling a first compartment of a multi-compartment applicator with afirst reactant,

filling a second compartment of said multi-compartment applicator with asecond reactant, said second reactant being capable of instantaneouslyreacting with said first component,

simultaneously dispensing the components of each of said compartmentsthrough a common location in a manifold into a mixing tip, from whichthe mixed components are applied to said site.

In the present method, the components may react to form a productselected from the group consisting of tissue sealant and epoxy glue. Ina further embodiment, the compartments of said applicator have the sameheight but different cross-sectional areas, said components react toform tissue sealant and the compartment with larger cross sectioncontains fibrin or fibrinogen solution. The applicator may have twocompartments, and the compartment with smaller cross section may containa thrombin solution.

Other features of the present invention will become apparent in thecourse of the following descriptions of the exemplary embodiments whichare given for illustration of the invention, and are not intended to belimiting thereof.

EXPERIMENTS EXAMPLE 1 Plasma Gel Made with Mixing Needle

One cubic centimeter of 300 millimolar calcium chloride solutioncontaining 100 units of bovine thrombin was loaded into the innercompartment of a coaxially arranged two compartment dispenserconstructed according to the design illustrated in FIG. 5. Ten cubiccentimeters of porcine plasma separated by centrifugation (1500×g for 15minutes) from whole blood collected in standard citrate anticoagulantsolution was loaded into the outer compartment. The cross-sectional areaof the outer compartment was 14.3 times greater than that of the innercompartment. The two solutions were expressed by pressing the button inthe center of the plungers and simultaneously depressing both plungers.The thrombin solution was extruded through a standard 22 gaugehypodermic needle housed within a standard 18 gauge hypodermic needle(which served as conduit for the expressed plasma) the arrangement shownin FIGS. 5 and 11. The two solutions merged within the outer needleapproximately 1 cm from the tip of the outer needle. The sealant wasextruded in this manner directly into cylindrical mold cavities of 9.3mm diameter and approximately 5 cm length. Coagulation of the extrudedfluid occurred within approximately 5 seconds. Approximately 5 minuteswere allowed to elapse between filling each of three molds. Nonoticeable increase in force was required to begin dispensing sealantinto the molds after these interruptions of flow. After 20 minutesincubation at room temperature to allow factor XIII mediatedcrosslinking of the molded gels, the gels were removed from their molds,clamped at either end and assembled into a device for measuring tensilestrength. Tensile strength was found to be 66±12 (mean±standarddeviation) grams per square centimeter.

EXAMPLE 2 Plasma Gel Film Made with Nebulizer

One cubic centimeter of 300 millimolar calcium chloride solutioncontaining 100 units of bovine thrombin was loaded into the innercompartment of a coaxially arranged two-compartment dispenserconstructed per the design represented by the illustration of FIGS. 5and 10. Ten cubic centimeters of porcine plasma separated bycentrifugation (1500×g for 15 minutes) from whole blood collected instandard citrate anticoagulant solution was loaded into the outercompartment. The cross-sectional area of the outer compartment was 14.3times greater than that of the inner compartment. The two solutions weredispensed by pressing the button in the center of the plungers andsimultaneously depressing both plungers. The thrombin-calcium solutionwas dispensed through the nebulizer tip shown in FIG. 8. The twosolutions merged within the tip and emerged as a fine spray which wasdeposited on glass. Microscopic examination of the film showed ahomogeneous thin layer of fibrin gel.

What is claimed as new and is desired to be secured by Letters Patent ofthe United States is:
 1. A manifold for combining first and secondcomponents of a material, comprising a body having first and secondinlet ports, a tubular dispenser coupled to the body and being providedwith an outlet and an internal passageway in fluid communication withsaid outlet, said body having first fluid transport means adapted fortransporting said first component from said first inlet port to saidinternal passageway and second fluid transport means adapted fortransporting said second component from said second inlet port to saidinternal passageway, said first fluid transport means including ahypodermic needle in fluid connection with said first inlet port andhaving an outlet disposed within said internal passageway, said secondfluid transport means including a channel in the body and in fluidconnection with said second inlet port and being provided with an outletdisposed within said internal passageway the hypodermic needle beinglocated in or being able to penetrate the channel whereby said first andsecond components are directed by said first and second transport meansinto said tubular dispenser for mixing prior to discharge from theoutlet of said tubular dispenser.
 2. The manifold of claim 1, wherein atleast part of said first fluid transport means is located within saidsecond fluid transport means.
 3. The manifold of claim 2, wherein atleast part of said first fluid transport means is concentricallydisposed within at least part of said second transport means.
 4. Themanifold of claim 1 wherein the tubular dispenser is a disposable tipconnected to said body which promotes mixing of said first and secondcomponents.
 5. The manifold of claim 1, further comprising means coupledto said manifold for atomizing effluent fluid from said manifold.
 6. Themanifold of claim 1, wherein said tubular dispenser is needle-like inconformation.
 7. A device for filling a dispenser having first andsecond fluid-tight compartments and an end portion provided with anoutlet port that communicates with the second compartment and having aneedle-like member extending from the end portion to an extremityprovided with an opening that communicates with the first compartment,comprising a body having an internal chamber and first and secondopposite end portions, a first fitting member adapted for attaching thebody to the dispenser provided at the first end portion of the body, afluid-tight membrane in communication with the internal chamberextending across the second end portion of the body, the fluid-tightmembrane made from a material which is puncturable by the needle-likemember, and a second fitting member carried by the body andcommunicating with the internal chamber whereby when the body isattached to the dispenser by means of the first fitting member theneedle-like member extends through the internal chamber of the body andthrough the fluid-tight membrane so that the opening in the extremity ofthe needle-like member is disposed outside of the body whereby theextremity of the needle-like member can engage a first container of afirst fluid for filling the first compartment of the dispenser and thesecond fitting member can engage a second container of a second fluidfor permitting the second fluid to pass through the internal chamber ofthe body and enter the outlet port to fill the second compartment. 8.The device of claim 7, wherein the body has a cylindrical side wallextending between the first and second end portions, the second fittingmember attached to the cylindrical side wall.
 9. The device of claim 7,wherein the flexible membrane is made from rubber.
 10. The device ofclaim 7, wherein the needle-like member has a length and the body has alength between first and second end portions which is less than thelength of the needle-like member.
 11. A static mixing apparatus for usewith a syringe assembly, comprising a tubular dispenser having a fluidinlet end portion and a fluid exit end portion, means carried by thefluid inlet end portion adapted to couple the tubular dispenser to thesyringe assembly, the tubular dispenser provided with a fluid passagewayextend therethrough from the fluid inlet end portion to the fluid exitend portion for carrying a fluid, a longitudinally-extending cylindricalmember disposed within the fluid passageway of said tubular dispenserand having a plurality of longitudinally spaced-apart rings providedwith respective gaps therein for forming a plurality of longitudinallyspaced-apart parallel arcs with adjacent arcs interconnected by a gapwhereby the arcs and gaps promote turbulent flow in the fluid to enhancemixing of said fluid.
 12. The mixing apparatus of claim 11 wherein eachgap is from 5 to 90°, the gap of one ring being located opposite the gapof an adjacent ring(s).
 13. The mixing apparatus of claim 11, furthercomprising a means for atomizing effluent fluid in fluid connection toone of said fluid inlet end portion and said fluid exit end portion ofthe tubular dispenser.